Various methods and compositions have been proposed for efficient delivery of therapeutic and diagnostic agents to their sites of action. One difficulty in the administration of such agents is the necessity for the drugs to remain in contact with the target tissue for a sufficient period of time, at a sufficient concentration to achieve the desired therapeutic or diagnostic effect. Such difficulties are particularly pronounced for compounds that must be administered by topical application, especially to fluid-associated tissues such as ocular tissue, nasal mucosa or the oral cavity. To illustrate, conventional ocular delivery systems such as eye drops often result in low bioavailability and poor therapeutic response because high tear fluid turnover and dynamics result in rapid precorneal elimination of the compounds. An increase in dosing frequency or the use of highly concentrated solutions to increase bioavailability is undesirable due to poor patient compliance and/or the risk of toxicity resulting from the systemic absorption of the drug via the nasolacrimal duct. Similar difficulties are encountered in administration of topical agents to other fluid-associated surface tissues, such as the nasal mucosa or oral cavity.
To address the problems associated with ocular drug delivery, various ophthalmic vehicles, such as suspension, ointments and inserts, have been investigated in attempts to extend the ocular residence time of drugs for topical applications to the eye. Such compositions have been applied directly to the conjunctiva or cul-de-sac of the eye to facilitate sustained retention of pharmaceutical agents contained therein on the surface of the eye.
Although these ocular delivery systems offer some improvement over conventional ophthalmic solutions, they have received poor patient compliance as a result of eye irritation due to particulate matter in suspensions, blurred vision caused by ointments, discomfort due to crusting of gels and ointments around the eye and difficulties associated with the placement and removal of inserts in the eye.
Another disadvantage of semi-solid gels or ointments is the tendency for these compositions to migrate within the cul-de-sac or to be lost from the eye. Additionally, such gels or ointments often persist in the ocular environment past the point at which all of the pharmaceutical compound has been delivered, thereby continuing to cause undesirable side effects such as crusting of the material and blurred vision.
Thus, from the point of view of patient compliance, a liquid ocular delivery system is most acceptable due to its ease of administration compared to the semi-solid gels and ointments described above. However, conventional liquid delivery systems are incapable of achieving the extended surface contact for sustained delivery of the diagnostic or therapeutic agent.
One approach to increasing the residence time of topically-applied drugs while enabling administration of the drugs in liquid form has been to develop delivery systems based on the concept of in situ gel formation. These delivery systems are made from polymers that exhibit phase transitions due to physico-chemical changes in their microenvironments. They can be instilled as liquid drops into the cul-de-sac of the eye, for example, where the microenvironment of the eye transforms the polymers into a gel or semi-solid phase. Similarly, liquid forms of the delivery systems can be introduced into the nasal mucosa, oral cavity or other physiological environment, wherein they would transform into a gel. Sustained release of ophthalmic drugs has been reported from gels and polymer matrices, and improved bioavailability and patient response to therapeutic agents has been shown in many cases. For example, Schoenwald et al., J. Pharm. Sci., 67: 1280-1283 (1978), showed that aqueous Carbopol.RTM. gels administered into rabbit eyes were retained for 4-6 hours and resulted in longer duration of action of incorporated pilocarpine compared to a viscous solution preparation (see also U.S. Pat. Nos. 4,271,143 and 4,407,792).
Subsequently, numerous in situ gel-forming delivery vehicles have been disclosed, which are based in changes in physico-chemical structure as a result of variations in temperature, pH, ionic strength, or a combination thereof. In U.S. Pat. No. 4,188,373, for example, a gel-forming drug delivery system is disclosed which utilizes proprietary non-ionic difunctional polyoxyalkyene derivatives of propylene glycol (known as Pluronic.RTM. polyols) as a thermally gelling polymer. The desired sol-gel transition temperature is said to be obtained by appropriate adjustment of the polymer concentration. Another thermally triggered system is disclosed in U.S. Pat. No. 4,474,751 and 4,474,752, which disclose an aqueous drug delivery system, based on proprietary non-ionic tetrafunctional polyoxyalkylene derivatives of ethylene diamine (known as Tetronic.RTM. polyols), which gel at temperatures from about 30.degree.-100.degree. C. The sol-gel transition temperature and rigidity of these gels are said to be capable of adjustment by changes in polymer concentration combined with the pH and ionic strength of the solution. These compounds contain from about 10% to about 50% by weight of Tetronic.RTM. polymers. Because of the adjustments to the solutions that must be made in order to produce a compound which sets at a physiologically useful temperature, the available viscosity range of such gelled products is limited.
As an alternative, in situ gel-forming compositions have been developed which gel in response to changes in pH. For example, U.S. Pat. No. 5,292,517 discloses a pH sensitive, reversible gelling copolymeric drug delivery system, which comprises an aqueous solution containing up to 25% (w/v) of poly (methylvinylether)/maleic acid) as the pH-sensitive gelling copolymer. These compositions are said to exhibit a sol-gel transition over physiologically compatible pH ranges.
Although successful in achieving increased drug retention times, the relatively high polymer concentration utilized in such thermally- or pH-sensitive gelling formulations undesirably increases the buffering capacity and the thermal energy needed to induce gelation of those formulations, leading to irritation and discomfort when used in the eye or other physiological target tissue. Moreover, the use of such high polymer concentrations is costly, and can retard the gelling process in situ, which can result in loss of the pharmaceutical agent from the site of administration during the lengthy time in which gelling occurs.
Addressing the difficulties associated with reversibly gelling compositions containing high concentrations of the gelling polymer, U.S. Pat. No. 5,252,318 discloses a reversibly gelling composition having a lower polymer concentration, which exhibits a sol-gel transition in response to simultaneous variation in two physical parameters, such as temperature and pH. The use of a combined polymer system that reversibly gels in response to two or more physico-chemical parameters is said to enable the formulation of in situ gelling compositions having a significantly reduced polymer concentration. While the reduction in polymer concentration solves the problems associated with high polymer concentration, the requirement for a composition that gels in response to simultaneous variations in at least two physical parameters limits the flexibility of formulating in situ gel-forming compositions, inasmuch as they must contain at least one pH-sensitive polymer and at least one thermally sensitive polymer.
Accordingly, a distinct advantage would be obtained by providing a reversibly gelling drug delivery composition comprising an aqueous solution of polymers at sufficiently low concentration to avoid the undesirable effects of high buffering capacity and slow induction of gelation, but which is not dependent on two independent physico-chemical parameters to achieve that result. Such a composition would retain the advantages of the two-parameter reversible gelling compositions described above, but would also enable greater flexibility in formulating in situ gelling compositions for delivery of a wide variety of diagnostic and therapeutic agents.